FDA Approves PDE-4 Inhibitor for COPD Flares

BY MICHELE G. SULLIVANK
Elsevier Global Medical News

Roflumilast was approved by the Food and Drug Administration March 1 to decrease the frequency of exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations.

The drug is the only PDE-4 inhibitor approved for this indication, according to Forest Pharmaceuticals, which developed the agent. It will be marketed as Daliresp and is expected to be commercially available later this year.

Roflumilast will be available in 500-mcg pills to be taken daily for the prevention of COPD exacerbations in patients with severe disease, according to the agency.

Its efficacy and safety were evaluated in eight clinical studies comprising 9,394 adult patients, of whom 4,425 took the drug, according to a statement issued by Forest. Two of these studies were 1-year placebo-controlled trials that together enrolled more than 3,100 patients. Those treated had a history of COPD associated with chronic bronchitis and had experienced an exacerbation of the disease during the 12 months before beginning treatment. All patients were taking concomitant medications, including longand short-acting beta-2 agonists, and/or short-acting anticholinergics.

Overall, the drug reduced the rate of moderate or severe exacerbations by 15% in one trial and 18% in the other, compared with placebo. The drug also improved prebronchodilator lung function.

Among the eight trials, most common adverse reactions in those taking the drug included diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite. Of patients taking roflumilast, 14% withdrew from the studies because of adverse events: 5% for gastrointestinal upset and the rest for other problems. Serious adverse events occurred in 14% of those taking placebo and 13% of those taking roflumilast. Death from COPD occurred in 20 patients in the roflumilast group and 22 in the placebo group – not a significant difference.

The company also noted that weight change occurred more often in those taking the drug. It occurred mostly in obese rather than underweight patients and caused no increased morbidity relative to placebo. However, the company warned in a 2010 FDA presentation, “Patients and physicians should be informed that weight loss is associated with roflumilast and weight should be regularly monitored.”

The drug is contraindicated in patients with moderate to severe liver impairment (Child-Pugh class B or C), according to the company’s statement

Other safety warnings that will appear on the packaging include:
•Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.
•Psychiatric events including suicidality are associated with its use, occurring in 5.9% of treated patients compared with 3.3% of those taking placebo. Three patients experienced suicide-related adverse reactions, with one completion and two attempts, compared with one suicidal ideation in one placebo-treated patient.
•The drug should not be used in conjunction with strong P450 enzyme inducers and used with caution in patients taking inhibitors of the CYP3A4 or CYP1A2 enzymes.
•Roflumilast should not be used by pregnant women unless the risks and benefits are carefully weighed, and should not be taken during labor and delivery.

The drug’s mechanism of action is not fully understood, the company noted. “It is thought to be related to the effects of increased intracellular adenosine monophosphate.”

COMMENTARY
Dr. Darcy Marciniuk, FCCP, comments: COPD exacerbations are a leading cause of hospitalization and mortality.We’ve had no new and effective therapeutic agents in COPD for years – this medication represents an important step forward. While the exact role roflumilast in the comprehensive management of COPD remains to be fully understood, any agent that further improves lung function and reduces exacerbations is welcome.